Cutibacterium acnes induces skin region-specific innate immune memory alterations in human keratinocytes

External insults can cause immune activation in immune cells, resulting in persistent molecular changes that can lead to innate immune memory (IIM) changes in these cells. This study investigated the potential for cellular reprogramming in response to Cutibacterium acnes in keratinocytes. We exposed normal human epidermal keratinocytes obtained by mammoplasty (NHEK-B) or abdominoplasty (NHEK-A) to C. acnes, followed by stimulation with Pam3CSK4 to assess immune activation and cellular responses. In NHEK-B cells, C. acnes and Pam3CSK4 treatment induced trained immunity-type responses, with higher expression of selected immune target genes, and a diminished response compared with that in nontrained but Pam3CSK4-induced NHEK-A cells. Total transcriptome analysis delineated regional differences, with the activation of immune-related pathways in NHEK-B cells and increased skin development in NHEK-A cells. We detected differences in metabolic regulation, and utilizing pharmacological inhibitors, we demonstrated the necessity of the optimal regulation of histone acetylation and DNA methylation for the aforementioned changes. This study demonstrated that C. acnes triggers IIM-like processes in keratinocytes, characterized by signaling, epigenetic, and metabolic reprogramming that influences cellular responses to subsequent stimuli. The observation that analogous insults might elicit skin region specific responses offers novel insights into the etiology and mechanisms underlying common inflammatory skin diseases.